Project 1. Defining Virologic and Immunologic Factors Predicting the Probability of Post-Treatment HIV Control

项目 1. 定义预测治疗后 HIV 控制概率的病毒学和免疫学因素

• 批准号: 9750628
• 负责人: Asier Saez-Cirion
• 金额: $ 21.66万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9750628
• 关键词: Acquired Immunodeficiency Syndrome; Address; Aftercare; Antiviral Agents; Antiviral Therapy; Blood; Cells; Characteristics; Chronic; Clinical; DNA; Data; Disease remission; Early treatment; Frequencies; Genetic; HIV; HIV Infections; HIV antiretroviral; HIV-1; Haplotypes; Immune response; Immune system; Immunologic Factors; Immunologics; Infection; Infection Control; Interruption; Knowledge; Life; Macaca; Maintenance; Patients; Pattern; Pharmaceutical Preparations; Predictive Factor; Primary Infection; Probability; SIV; Sampling; Shapes; Therapeutic Intervention; Time; Tissues; Viral; Viral reservoir; Viremia; Virus; Withholding Treatment; antiretroviral therapy; cohort; immune activation; mathematical model; nonhuman primate; outcome prediction; pathogen; patient population; predictive marker; preservation; treatment duration; treatment effect; viral rebound; virology

ABSTRACT Antiretroviral therapy blocks HIV replication, but is not curative, as quiescent integrated HIV DNA is not eradicated by classical drugs. HIV reservoirs of latently infected cells persist indefinitely in infected patients even after long-term periods of treatment and cause rapid viral rebound if the treatment is stopped. Our identification of some patients who were able to durably control viremia after therapy discontinuation (Post- Treatment Controllers, PTCs) introduced the concept of sustained HIV remission and provided proof of concept that such status is achievable at least in some patients. HIV remission in PTCs is characterized by the presence of infected cells, although at low levels. This implies that this situation of long-term viral control requires balanced interactions between HIV-1 and the host. Yet, intriguingly, PTCs do not have the genetic, clinical or immunological characteristics that are commonly found in the rare patients able to naturally control HIV-1 without therapeutic intervention (HIV controllers). HIV remission appears to be favored by the early initiation of antiretroviral treatment and its maintenance for several years before discontinuation. We believe that PTCs benefited from an early treatment that limited the establishment of viral reservoirs and allowed optimal maturation/priming and preservation of critical immune responses. However, only a small fraction of early and durably treated patients are able to control infection after treatment interruption. There is therefore an urgent need to identify the precise mechanisms associated with post-treatment control of infection and define biomarkers that predict the outcome of cART discontinuation. For this, it will be essential to better understand (i) the dynamics of the establishment and maintenance of cellular HIV reservoirs, (ii) the interplay between immune responses and infected cells, and (iii) the impact of early cART on these parameters. We will compare immunological and virological parameters in PTCs and in patients on effective long-term cART, initiated during primary or chronic HIV-infection. We will use empirical analyses and mathematical modeling to (i) define correlates of protection that could identify ART-receiving patients with the highest probability to achieve HIV remission; and (ii) provide a detailed characterization of the effect of treatment initiation on the pattern and the size of the viral reservoirs and immune responses and how this impact the dynamics of viral rebound at the time of treatment initiation. To develop this project we will benefit of access to unique samples from patients in ANRS PRIMO and ANRS VISCONTI Cohorts and to the empirical data generated in a large non-human primate study of 66 SIV-infected macaques initiating cART at different times and maintaining the treatment for 2 years before interruption.

摘要 抗逆转录病毒疗法阻止艾滋病毒复制，但不是治愈的，因为静止的整合艾滋病毒DNA不是 被经典药物根除。潜伏感染细胞的HIV蓄水池在感染患者中无限期存在 即使在长期治疗后，如果停止治疗，也会引起病毒的快速反弹。我们的 一些患者在停止治疗后能够持久地控制病毒血症(后 治疗控制员(PTC)引入了艾滋病毒持续缓解的概念，并提供了 这一概念认为，至少在某些患者中可以达到这种状态。PTCS中的HIV缓解的特点是 存在受感染的细胞，尽管水平较低。这意味着这种长期病毒控制的情况 需要艾滋病毒-1和宿主之间的平衡相互作用。然而，耐人寻味的是，PTC没有遗传， 在能够自然控制的罕见患者中常见的临床或免疫学特征 没有治疗干预的艾滋病毒-1(艾滋病毒控制员)。艾滋病病毒的缓解似乎受到早期患者的青睐 开始抗逆转录病毒治疗并维持数年，然后停止治疗。我们相信 PTC受益于早期治疗，限制了病毒库的建立，并允许 关键免疫反应的最佳成熟/启动和保存。然而，只有一小部分 早期和持久治疗的患者能够在治疗中断后控制感染。因此，有一种 迫切需要确定与治疗后感染控制有关的确切机制，并确定 预测CART停药结果的生物标志物。为此，有必要更好地理解 (1)建立和维持细胞艾滋病毒储存库的动态；(2) 免疫反应和感染细胞，以及(Iii)早期CART对这些参数的影响。 我们将比较PTC患者和长期有效患者的免疫学和病毒学参数。 在原发或慢性HIV感染期间启动的CART。我们将使用实证分析和数学方法 建模以(I)定义可以识别接受抗逆转录病毒治疗的患者的保护相关因素 实现艾滋病毒缓解的可能性；和(2)提供治疗效果的详细特征 关于病毒库和免疫反应的模式和大小的启动，以及这如何影响 治疗开始时病毒反弹的动态。为了开发这个项目，我们将受益于访问 ANRS Primo和ANRS Visconi队列中患者的独特样本以及经验数据 在对66只感染SIV的猕猴在不同时间启动手推车的大型非人类灵长类动物研究中产生的 停药前维持治疗2年。